We are synthesizing opioids incorporating peptidomimetics and pairwise retro-inverso modifications as part of constrained peptide structures. These target molecules are chosen with the aid of computer simulations. Prior work in related areas has allowed us to proposed model structures to explain selectivity among the classes of opioid receptors. Target enkephalin analogs incorporating peptidomimetic sequences have already been prepared based on the structure of the highly active opiate Tyr-c[D-A2bu- Gly-Phe-Leu]. In this application, we apply these findings an describe the syntheses of various novel families of potentially selective an highly active opioids. Future target molecules will include analogs of dermorphin in which phenylalanine is substituted for glycine at the third position. These molecules will allow us to explore the interaction among the aromatic rings of phenylalanines and tyrosine already shown to be important for selectivity at the opiate receptors. Other retro-inverso modified enkephalins will have alpha-aminoisobutyryl residues at positions two and five. Another set of constrained analogs involve cis and tras 2- aminocyclopentane carboxylic acid,, a proline-like residue at the second position in order to probe the role of cis and trans stereoisomers in biological activity. Our program also encompasses the synthesis of six- membered retro-inverso cyclic dimers in order to search for the minimum structural requirements necessary for activity and affinity with the opiate receptors. Many of these constrained molecules exhibit strong conformational preferences. Where appropriate the conformational characterizations of the compounds will be carried out using NM and computer simulations. The NM studies involve the most up to date two dimensional measurements and temperature and solvent effects on conformations. The computer simulations include flexible geometry energy minimizations and molecular dynamics. The biological profiles of all target molecules are examined by binding and receptor tissue assays. From these findings we hope to develop new opioid drug candidates.